JP6096797B2 - 3−シアノアリール−1H−ピラゾロ[2.3−b]ピリジン誘導体 - Google Patents
3−シアノアリール−1H−ピラゾロ[2.3−b]ピリジン誘導体 Download PDFInfo
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- JP6096797B2 JP6096797B2 JP2014542726A JP2014542726A JP6096797B2 JP 6096797 B2 JP6096797 B2 JP 6096797B2 JP 2014542726 A JP2014542726 A JP 2014542726A JP 2014542726 A JP2014542726 A JP 2014542726A JP 6096797 B2 JP6096797 B2 JP 6096797B2
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- pyrrolo
- pyridin
- tetrahydropyran
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Description
本発明の目的は、有用な特性を有する新規な化合物、特に医薬の調製に使用することができるものを見出すことにあった。
本発明は、1種または2種以上のキナーゼを阻害することが可能であるピリジン化合物に関する。当該化合物を、癌、敗血症性ショック、原発性開放隅角緑内障(POAG)、過形成、関節リウマチ、乾癬、アテローム性動脈硬化症、網膜症、骨関節炎、子宮内膜症、慢性炎症および/または神経変性疾患、例えばアルツハイマー病を含む多様な障害の処置において使用する。
文献:
Y.-H.Ou et al., Molecular Cell 41, 458-470, 2011;
D.A. Barbie et al., Nature, 1-5, 2009。
腫瘍はさらに、単球性白血病、脳、泌尿生殖器、リンパ系、胃、喉頭ならびに肺腺癌および小細胞肺癌を含む肺癌、膵臓および/または乳癌を含む。
本明細書中での用語「防止」は、有機体が最初の段階で障害または疾患を得るのを阻止する方法を指す。
他のベンゾニトリル誘導体は、TBK1および/またはIKKε阻害剤としてWO 2011/046970 A1に記載されている。
WO 2005/095400には、他のアザインドールキナーゼ阻害剤が記載されている。
WO2006/015123には、他のピロロピリジンキナーゼモジュレーターが記載されている。
さらなるピリジンおよびピラジン誘導体は、癌の処置のための使用においてWO 2009/053737に、および他の疾患の処置のためにWO 2004/055005に記載されている。
ピロロピリミジンは、IKKεおよびTBK1阻害剤としてWO 2010/100431に記載されている。
ピリミジン誘導体は、IKKεおよびTBK1阻害剤としてWO 2009/030890に記載されている。
本発明は、式I
XはCHまたはNを示し、
R1はH、AまたはCycを示し、
R2はO[C(R6)2]nHet1、NR6[C(R6)2]nHet1、O[C(R6)2]nCycまたはNR6[C(R6)2]nCycを示し、
R3はH、Hal、A、OR6、N(R6)2、O[C(R6)2]mN(R6)2、O[C(R6)2]nHet2、NR6[C(R6)2]mN(R6)2、NR6[C(R6)2]nHet2、ArまたはHet2を示し、
R4はHまたはOR6を示し、
R5はHまたはOR6を示し、
R6はHまたは1〜6個のC原子を有する非分枝状もしくは分枝状アルキルを示し、ここで1〜7個のH原子はFによって置き換えられていてもよく、
Cycは、3、4、5、6または7個のC原子を有し、非置換であるか、またはCNもしくはAによって単置換されている環状アルキルを示し、
HalはF、Cl、BrまたはIを示し、
mは1、2または3を示し、
nは0、1または2を示し、
pは0、1、2、3または4を示す、
で表される化合物、ならびにそれらの薬学的に使用可能な塩、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物に関する。
本発明は、必然的にまた塩の溶媒和物に関する。
プロドラッグ誘導体は、例えばアルキル基もしくはアシル基、糖またはオリゴペプチドにより修飾され、生物体中で迅速に切断されて本発明の有効な化合物を形成する、式Iで表される化合物を意味するものと解釈される。
これらはまた、例えばInt. J. Pharm. 115, 61-67 (1995)に記載されているように、本発明の化合物の生分解性ポリマー誘導体を含む。
さらに、「治療的有効量」の表現は、この量を施与されていない対応する対象と比較して、以下の結果:
疾患、症候群、状態、愁訴、障害もしくは副作用の改善された処置、治癒、防止もしくは解消、あるいはまた疾患、状態もしくは障害の進行の低減
を有する量を示す。
表現「治療的有効量」はまた、正常な生理学的機能を増大させるのに有効である量を包含する。
これらは、特に好ましくは立体異性体化合物の混合物である。
YはBrまたはIを示し、
Qは保護基を示す、
で表される化合物を
式III
Lはボロン酸ラジカルまたはボロン酸エステル基を示す、
で表される化合物と反応させ、
Qをその後切断して除去するか、
あるいは
かつ/あるいは式Iで表される塩基または酸をその塩の1種に変換する
ことを特徴とする、前記方法に関する。
Aは、特に好ましくは1〜8個のC原子を有し、ここでさらに1つもしくは2つの隣接していないCHおよび/もしくはCH2基は、Nおよび/もしくはO原子によって置き換えられていてもよく、かつ/または1〜7個のH原子は、Fによって置き換えられていてもよい非分枝状または分枝状アルキルを示す。
シクロアルキル(環状アルキル)は、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロヘプチルを示す。
R2は好ましくはO[C(R6)2]nHet1またはO[C(R6)2]nCycを示す。
R3は好ましくはH、Hal、O[C(R6)2]nHet2、ArまたはHet2を示す。
R4は、特に好ましくはHを示す。
R5は、特に好ましくはHを示す。
R6は好ましくはHまたはメチルを示す。
Halは、好ましくはF、ClまたはBr、しかしまたI、特に好ましくはFまたはClを示す。
式Iで表される化合物は、1つまたは2つ以上のキラル中心を有していてもよく、したがって様々な立体異性体形態で存在し得る。式Iは、すべてのこれらの形態を包含する。
Ibにおいて、R3は、H、Hal、O[C(R6)2]nHet2、ArまたはHet2を示し;
Ifにおいて、Aは、1〜8個のC原子を有し、ここで1つもしくは2つの隣接していないCHおよび/もしくはCH2基がNおよび/もしくはO原子によって置き換えられていてもよく、かつ/またはさらに1〜7個のH原子がFによって置き換えられていてもよい非分枝状または分枝状アルキルを示し;
R1はH、AまたはCycを示し、
R2はO[C(R6)2]nHet1またはO[C(R6)2]nCycを示し、
R3はH、Hal、O[C(R6)2]nHet2、ArまたはHet2を示し、
R4はHまたはOR6を示し、
R5はHまたはOR6を示し、
R6はHまたはメチルを示し、
Aは、1〜8個のC原子を有し、ここで1つもしくは2つの隣接していないCHおよび/もしくはCH2基がNおよび/もしくはO原子によって置き換えられていてもよく、かつ/またはさらに1〜7個のH原子がFによって置き換えられていてもよい非分枝状または分枝状アルキルを示し;
HalはF、Cl、BrまたはIを示し、
mは1、2または3を示し、
nは0、1または2を示し、
pは0、1、2、3または4を示す、
ならびにそれらの薬学的に使用可能な塩、互変異性体および立体異性体であり、すべての比率におけるそれらの混合物を含む。
式IIおよび式IIIで表される化合物は、一般的に知られている。しかしながら、それらが新規である場合には、それらを、自体知られている方法によって製造することができる。
式IIIで表される化合物において、Lは、好ましくは
当該反応を、当業者にSuzukiの条件またはSuzuki反応として知られている条件の下で行う。
特に好ましいのはDMFおよび水である。
例えばメチルエーテルのエーテル切断の標準的な方法は、三臭化ホウ素の使用である。
窒素上でのアルキル化を、当業者に知られているように標準的な条件の下で行う。
フェニルスルホニル基を、好ましくはTHF中のトリフルオロエタノールまたはメタノールを使用して、有機または無機塩基の添加を伴って切断する。
XはCHまたはNを示し、
Qはtert−ブトキシカルボニルまたはフェニルスルホニルを示し、
R1はH、AまたはCycを示し、
R2はO[C(R6)2]nHet1またはO[C(R6)2]nCycを示し、
R3はH、Hal、O[C(R6)2]nHet2、ArまたはHet2を示し、
R4はHまたはOR6を示し、
R5はHまたはOR6を示し、
R6はHまたはメチルを示し、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1つもしくは2つの隣接していないCHおよび/もしくはCH2基は、Nおよび/もしくはO原子によって置き換えられていてもよく、かつ/またはさらに、1〜7個のH原子は、Fによって置き換えられていてもよく、
HalはF、Cl、BrまたはIを示し、
mは1、2または3を示し、
nは0、1または2を示し、
pは0、1、2、3または4を示す、
で表される化合物、ならびにそれらの薬学的に使用可能な塩、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物に関する。
本発明の前述の化合物を、それらの最終的な非塩形態で用いることができる。一方、本発明はまた、これらの化合物を、当該分野で公知の手順によって、種々の有機および無機酸類および塩基類から誘導し得るそれらの薬学的に許容し得る塩の形態で用いることを包含する。式Iで表される化合物の薬学的に許容し得る塩の形態は、大部分、慣用的な方法によって製造される。式Iで表される化合物がカルボキシル基を含む場合は、この好適な塩の1種を、当該化合物を好適な塩基と反応させて対応する塩基付加塩を得ることによって生成することができる。このような塩基は、例えば、水酸化カリウム、水酸化ナトリウムおよび水酸化リチウムを含むアルカリ金属水酸化物;アルカリ土類金属水酸化物、例えば水酸化バリウムおよび水酸化カルシウム;アルカリ金属アルコキシド類、例えばカリウムエトキシドおよびナトリウムプロポキシド;ならびに種々の有機塩基、例えばピペリジン、ジエタノールアミンおよびN−メチルグルタミンである。
局所投与に適合した医薬化合物を、軟膏、クリーム、懸濁液、ローション、散剤、溶液、ペースト、ゲル、スプレー、エアゾールまたは油として処方することができる。
口における局所的適用に適合した医薬処方物は、薬用キャンディー、トローチおよび洗口剤を包含する。
直腸内投与に適合した医薬処方物を、坐剤または浣腸剤の形態で投与することができる。
膣内投与に適合した医薬処方物を、膣坐薬、タンポン、クリーム、ゲル、ペースト、発泡体またはスプレー処方物として投与することができる。
(a) 有効量の式Iで表される化合物ならびに/またはそれらの薬学的に使用可能な塩、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物、
ならびに
(b) 有効量のさらなる医薬活性化合物
の別個のパックからなるセット(キット)に関する。
ならびに、溶解した形態または凍結乾燥形態での有効量のさらなる医薬活性化合物
を含む個別のアンプルを含んでもよい。
本発明は、癌、敗血症性ショック、原発性開放隅角緑内障(POAG)、過形成、関節リウマチ、乾癬、アテローム性動脈硬化症、網膜症、骨関節炎、子宮内膜症、慢性炎症および/または神経変性疾患、例えばアルツハイマー病の処置のための使用のための式Iで表される化合物に関する。
宿主または患者は、あらゆる哺乳動物種、例えば霊長類種、特にヒト;マウス、ラットおよびハムスターを含むげっ歯動物;ウサギ;ウマ、ウシ、イヌ、ネコなどに属し得る。動物モデルは、ヒト疾患の処置のためのモデルを提供する実験的調査に興味深い。
固形腫瘍は、好ましくは扁平上皮、膀胱、胃、腎臓、頭頸部、食道、子宮頸部、甲状腺、腸、肝臓、脳、前立腺、尿生殖路、リンパ系、胃、喉頭および/または肺の腫瘍の群から選択される。
好ましいのは、さらに、血液および免疫系の腫瘍の処置のための、好ましくは急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病および/または慢性リンパ性白血病の群から選択された腫瘍の処置のための使用である。
IKKε−キナーゼアッセイ(IKKエプシロン)
概要
キナーゼアッセイを、348ウェルフラッシュプレート(FlashPlates)アッセイとして(例えばTopcount測定について)行う。
1nMのIKKε、800nMのビオチン化IκBα(19−42)ペプチド(ビオチン−C6−C6−GLKKERLLDDRHDSGLDSMKDEE)および10μMのATP(0.3μCiの33P−ATP/ウェルを添加した)を、50μl(10mMのMOPS、10mMの酢酸Mg、0.1mMのEGTA、1mMのジチオトレイトール、0.02%のBrij35、0.1%のBSA、0.1%のBioStab、pH7.5)の全容積において30℃で2時間、試験化合物と共に、または試験化合物なしでインキュベートする。反応を、25μlの200mMのEDTAを使用して停止する。室温で30分後、液体を除去し、各ウェルを、100μlの0.9%塩化ナトリウム溶液で3回洗浄する。非特異的反応を、3μMのMSC2119074(BX−795)の存在下で決定する。放射能を、TopCount(PerkinElmer)を使用して測定する。結果(例えばIC50値)を、IT Departmentによって提供されるプログラムツール(例えばAssayExplorer, Symyx)を使用して計算する。
酵素試験
概要
キナーゼアッセイを、348ウェルフラッシュプレートアッセイとして(例えばTopcount測定について)行う。
0.6nMのTANK結合キナーゼ(TBK1)、800nMのビオチン化MELK誘導ペプチド(ビオチン−Ah−Ah−AKPKGNKDYHLQTCCGSLAYRRR)および10μMのATP(0.25μCiの33P−ATP/ウェルを添加した)を、30℃で120分間、50μl(10mMのMOPS、10mMの酢酸Mg、0.1mMのEGTA、1mMのDTT、0.02%のBrij35、0.1%のBSA、pH7.5)の全容積において、試験化合物と共に、または試験化合物なしでインキュベートする。反応を、25μlの200mMのEDTAで停止する。室温で30分後、液体を除去し、各ウェルを、100μlの0.9%塩化ナトリウム溶液で3回洗浄する。非特異的反応を、100nMのスタウロスポリンの存在下で測定する。放射能を、TopCount(PerkinElmer)において測定する。結果(例えばIC50値)を、IT Departmentによって提供されるプログラムツール(例えばAssayExplorer, Symyx)を使用して計算する。
Ser386におけるホスホ−IRF3の用量応答阻害
細胞/MDAMB468/INH/PHOS/IMAG/pIRF3
1. 範囲
TBK1およびIKKεが主として固有の免疫応答における重要な物質として知られているが、最近の発見は、TBK1およびIKKεについてのRas誘発発癌性形質転換における役割を示した。TBK1は、Ras誘発形質転換に必要であるRas様(Ral)−グアニンヌクレオチド交換因子(GEF)経路におけるRalBエフェクターであると確認された。TBK1は、リン酸化の際にホモ二量体化し、核に対して転位置させるIRF3を直接活性化し、ここでそれは、炎症、免疫調節、細胞生存および増殖と関連するプロセスを活性化する。
ポリイノシン−ポリシチジル酸(ポリ(I:C)、二重らせんRNA(dsRNA)の合成類似体、ウイルス感染と関連し、Toll様受容体3(TLR3)によって認識された分子パターンでの処理を使用して、Ser386でのTBK1/IKKε活性およびIRF3リン酸化を誘発する。
1日目:MDA−MB−468細胞を、HyQ−Taseを使用して脱離させ、計数し、TC表面および透明な底を備えた384ウェルプレート中に、ウェルあたり10,000個の細胞の密度において、35μlの完全培地の全容積において播種する。あるいはまた、細胞を、凍結したガラスバイアルから直接播種する。
細胞:ATCC HTB 132、Burger Lab(MP−CB 2010−327またはMDA−MB−468/10)
蒔く培地=培養培地:
RPMI 1640、Invitrogen # 31870
10%のFCS、Invitrogen # 10270-106
2mMのGlutamax、Invitrogen #35050-038
1mMのピルビン酸ナトリウム、Invitrogen # 11360
1%のPen/Strep
37℃、5%のCO2
サブ培養(subcultivation):HyQ-Tase、Thermo Scientific (HyClone) # SV30030.01
ポリ(I:C)(LMW)、Invitrogen # tlrl-picw(20mg/mlの原液を無菌PBS中に調製し、30分間55℃で水浴中で変性させ、RTにゆっくり冷却し、−20℃でアリコート中に保存する)
基準阻害剤:MSC2119074A−4=BX−795(IC50:200〜800nM)
阻害対照:10μMのMSC2119074A−4=BX−795
中性の対照:0.5%のDMSO
MSC2119074A−4=BX−795での10点用量反応曲線は、各実験中に含まれる。
PBS 1×DPBS、Invitrogen # 14190
ホルムアルデヒド(メタノール非含有、16%、超高純度EM等級)、Polysciences # 18814(保存RT)、最終濃度:4%
メタノール、Merck # 1.06009.1011(−20℃、前冷却)
ヤギ血清、PAA # B15-035(保存4℃、長期間−20℃)、最終濃度:10%
BSA(IgGおよびプロテアーゼ非含有、30%)、US-Biological # A1317(保存4℃、長期間−20℃)、最終濃度:2%
抗pIRF−3ウサギmAb、Epitomics # 2526-B(保存−20℃)、最終濃度:1:2000、PBS/2%のBSA中
Alexa Fluorヤギ抗ウサギ−488、Invitrogen # A11034または# A11008(保存4℃、暗中)、最終濃度:1:2000、PBS/2%のBSA/0.1%のTween中
プロピジウムヨージド(PI)、Fluka # 81845、H2O中1mg/ml(保存4℃、暗中)、最終濃度:0.2μg/ml
HPLC/MS条件A
カラム:Chromolith Performance ROD RP-18e、100×3mm2
勾配:A:B=99:1〜0:100、3.5分において
流量:2.0ml/分
溶離剤A:水+0.05%のギ酸
溶離剤B:アセトニトリル+0.04%のギ酸
波長:220nm
質量分析:正のモード
カラム:Chromolith Performance ROD RP-18e、50×4.6mm2
勾配:A:B=96:4〜0:100、2.8分において
流量:2.40ml/分
溶離剤A:水+0.05%のギ酸
溶離剤B:アセトニトリル+0.04%のギ酸
波長:220nm
質量分析:正のモード
カラム:Chromolith Performance ROD RP-18e、100×3mm2
勾配:A:B=99:1〜0:100、1.8分において
流量:2.0ml/分
溶離剤A:水+0.05%のギ酸
溶離剤B:アセトニトリル+0.04%のギ酸
波長:220nm
質量分析:正のモード
5−(1H−ピロロ[2,3−b]ピリジン−3−イル)−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A1」)の調製を、以下のスキームと同様にして行う:
5−(4−メトキシ−1H−ピロロ[2,3−b]ピリジン−3−イル)−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A2」)
HPLC/MS(A):1.85分、[M+H] 350;
HPLC/MS(A):2.71分、[M+H] 350。
5−[5−(1−メチルピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A4」)の調製を、以下のスキームと同様にして行う:
5−(5−ブロモ−1H−ピロロ[2,3−b]ピリジン−3−イル)−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A5」)の調製を、以下のスキームと同様にして行う:
5−[5−(4−シアノフェニル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A6」)の調製を、以下のスキームと同様にして行う:
5−[5−[1−(2−モルホリノエチル)ピラゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A7」)
HPLC/MS(B):1.55分、[M+H] 499;
HPLC/MS(B):2.26分、[M+H] 481;
HPLC/MS(A):1.83分、[M+H] 483;
HPLC/MS(A):2.30分、[M+H] 444;
5−[2−メチル−5−(1−メチルピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A11」)の調製を、以下のスキームと同様にして行う:
さらなる生成物を、硫酸ナトリウムでの乾燥および蒸発の後に有機相から単離する。
5−[5−(1−ピペリジン−4−イル−1H−ピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−(テトラヒドロピラン−4−イルオキシ)ベンゾニトリル(「A12」)の調製を、以下のスキームと同様にして行う:
2−(1−メチルピペリジン−4−イルオキシ)−5−[5−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]ベンゾニトリル(「A13」)および5−(5−ブロモ−1H−ピロロ[2,3−b]ピリジン−3−イル)−2−(シクロプロピルメトキシ)ベンゾニトリル(「A14」)の調製を、以下のスキームと同様にして行う:
5−[5−[1−(2−ヒドロキシエチル)ピラゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A15」)の調製を、以下のスキームと同様にして行う:
5−[5−[1−(1−メチル−4−ピペリジル)ピラゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A16」)の調製を、以下のスキームと同様にして行う:
5−[5−(4−メチルピペラジン−1−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A17」)の調製を、以下のスキームと同様にして行う:
5−[5−[1−(4−ピペリジル)ピラゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシピリジン−3−カルボニトリル(「A18」)、
5−[5−[1−[1−(ベンゼンスルホニル)−4−ピペリジル]ピラゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシピリジン−3−カルボニトリル(「A19」)および
5−[5−[1−(1−メチル−4−ピペリジル)ピラゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A20」)
の調製を、以下のスキームと同様にして行う:
5−[5−(2−モルホリノエトキシ)−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A21」)の調製を、以下のスキームと同様にして行う:
5−[5−[1−(4−ピペリジル)トリアゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A22」)および5−[5−[1−(1−メチル−4−ピペリジル)トリアゾール−4−イル]−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−テトラヒドロピラン−4−イルオキシベンゾニトリル(「A23」)の調製を、以下のスキームと同様にして行う:
5−[5−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]−2−(オキセタン−3−イルオキシ)ベンゾニトリル(「A31」)の調製を、以下のスキームと同様にして行う:
2−(オキセタン−3−イルオキシ)−5−[5−(1−オキセタン−3−イル−1H−ピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]ベンゾニトリル(「A34」)の調製を、以下のスキームと同様にして行う:
2−(3−メチルオキセタン−3−イルメトキシ)−5−[5−(1−オキセタン−3−イル−1H−ピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]ベンゾニトリル(「A35」)および2−(3−メチルオキセタン−3−イルメトキシ)−5−[5−(1H−ピラゾール−4−イル)−1H−ピロロ[2,3−b]ピリジン−3−イル]ベンゾニトリル(「A36」)の調製を、以下のスキームと同様にして行う:
例A:注射バイアル
100gの本発明の活性化合物および5gのリン酸水素二ナトリウムを3lの2回蒸留水に溶解させた溶液を、2N塩酸を用いてpH6.5に調整し、滅菌濾過し、注射バイアル中に移し、滅菌条件下で凍結乾燥させ、滅菌条件下で密封する。各々の注射バイアルは、5mgの活性化合物を含む。
20gの本発明の活性化合物の100gの大豆レシチンおよび1400gのココアバターとの混合物を、溶融し、型中に注入し、放冷する。各々の座剤は、20mgの活性化合物を含む。
940mlの2回蒸留水中の1gの本発明の活性化合物、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムから、溶液を調製する。pHを6.8に調整し、溶液を1lにし、放射線により滅菌する。この溶液を、点眼剤の形態で用いることができる。
500mgの本発明の活性化合物を、99.5gのワセリンと、無菌条件下で混合する。
1kgの活性化合物、4kgのラクトース、1.2kgのジャガイモデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、慣用の方法で圧縮して、錠剤を得、各々の錠剤が10mgの活性化合物を含むようにする。
例Eと同様にして、錠剤を圧縮し、次に、慣用の方法で、スクロース、ジャガイモデンプン、タルク、トラガカントおよび染料の被膜で被覆する。
2kgの活性化合物を、硬質ゼラチンカプセル中に、慣用の方法で導入して、各々のカプセルが20mgの活性化合物を含むようにする。
1kgの本発明の活性化合物を60lの2回蒸留水に溶解させた溶液を、滅菌濾過し、アンプル中に移送し、滅菌条件下で凍結乾燥させ、滅菌条件下で密封する。各々のアンプルは、10mgの活性化合物を含む。
Claims (5)
- 以下の群
- 請求項1に記載の少なくとも1種の化合物および/またはそれらの薬学的に使用可能な塩、互変異性体または立体異性体、あるいはすべての比率でのそれらの混合物、ならびに、任意に賦形剤および/または補助剤を含む、医薬。
- 癌、敗血症性ショック、原発性開放隅角緑内障(POAG)、過形成、アテローム性動脈硬化症、網膜症、骨関節炎、子宮内膜症、慢性炎症、神経変性疾患、関節リウマチ(RA)、全身性エリテマトーデス(SLE)、シェーグレン症候群、アイカルディ・グティエール症候群凍瘡状、網膜の脈管障害、大脳白質ジストロフィー(RVCL)、全身性硬化症、筋炎、乾癬、慢性閉塞性肺疾患(CPD)、炎症性腸疾患(IBD)、肥満、インスリン抵抗性、2型糖尿病(NIDDM)および/またはメタボリックシンドロームの処置のための使用のための、請求項1に記載の化合物、ならびにそれらの薬学的に使用可能な塩、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物。
- 請求項1に記載の治療的に有効な量の化合物を、1)エストロゲン受容体モジュレーター、2)アンドロゲン受容体モジュレーター、3)レチノイド受容体モジュレーター、4)細胞毒性薬、5)抗増殖剤、6)プレニル−タンパク質転移酵素阻害剤、7)HMG−CoA還元酵素阻害剤、8)HIVプロテアーゼ阻害剤、9)逆転写酵素阻害剤および10)さらなる血管新生阻害剤の群からの化合物と組み合わせて投与する、腫瘍の処置のための使用のための請求項1に記載の化合物、ならびに/またはそれらの生理学的に許容し得る塩、互変異性体および立体異性体。
- 請求項1に記載の治療的に有効な量の化合物を、放射線療法および1)エストロゲン受容体モジュレーター、2)アンドロゲン受容体モジュレーター、3)レチノイド受容体モジュレーター、4)細胞毒性薬、5)抗増殖剤、6)プレニル−タンパク質転移酵素阻害剤、7)HMG−CoA還元酵素阻害剤、8)HIVプロテアーゼ阻害剤、9)逆転写酵素阻害剤および10)さらなる血管新生阻害剤の群からの化合物と組み合わせて投与する、腫瘍の処置のための使用のための請求項1に記載の化合物、ならびに/またはそれらの生理学的に許容し得る塩、互変異性体および立体異性体。
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PCT/EP2012/004543 WO2013075785A1 (de) | 2011-11-22 | 2012-10-30 | 3-cyanaryl-1h-pyrrolo[2,3-b]pyridin-derivate |
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CN106715419A (zh) | 2014-09-26 | 2017-05-24 | 吉利德科学公司 | 用作tank‑结合激酶抑制剂化合物的氨基三嗪衍生物 |
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US10316049B2 (en) | 2015-12-17 | 2019-06-11 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
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DE102016113714A1 (de) | 2016-07-26 | 2018-02-01 | Rosa Karl | Transfektionsverfahren mit nicht-viralen Genliefersystemen |
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AU2012342891A1 (en) | 2014-07-03 |
CA2856357A1 (en) | 2013-05-30 |
DE102011119127A1 (de) | 2013-05-23 |
AU2012342891B2 (en) | 2016-10-13 |
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AR088925A1 (es) | 2014-07-16 |
IL232717B (en) | 2018-08-30 |
CA2856357C (en) | 2019-10-01 |
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